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Talk about something coming out of left field. Chronic fatigue syndrome (ME/CFS) isn’t the only condition that produces odd and puzzling responses to exercise. It turns out that people with rheumatoid arthritis (RA) have their own mysterious problems with exercise.

fatigued-woman-after-exercise

Exercise intolerance doesn’t just occur in ME/CFS. It’s also found in rheumatoid arthritis.

That doesn’t make sense. Yes, the swollen and painful joints found in RA present impediments to exercise but the joints aren’t the problem for people. People with RA find that exercise – often thought of as a universal healer – leaves them feeling “drained” and fatigued. Just as people with ME/CFS do, people with RA are exhibiting some sort of systemic exercise intolerance.

Fatigue is a big – and mysterious – issue in RA as well. Fatigue is common, yet the medications which improve the joint problems in RA have small or quite modest effects on fatigue. Despite the “the tremendous impact of fatigue on patient health and quality of life”, the consensus seems to be that fatigue is not a product of the disease itself but is caused by outside factors such as “obesity, physical inactivity, sleep disturbance, and depression”. Indeed, little research has attempted to understand the cause of fatigue in RA, and things like exercise, cognitive behavioral therapy, and mindfulness are recommended to treat it.

(A large, two-year UK CBT trial found that CBT was found to be helpful by patients but produced only moderate results (19% reduction in fatigue and self-care) at best. Persistent fatigue was still present.)

If RA is an autoimmune/inflammatory disease that attacks the joints, why are exercise intolerance and fatigue so common? The not-so-obvious answer is that RA is not just an immune disease that attacks the joints. It’s an immune disease that does other things as well -and that includes producing a lot of fatigue, and some kind of exercise intolerance.

That makes it very interesting for people with ME/CFS.

The Study

“…these differences suggest that sympathetic overactivation may be a hallmark in RA pathophysiology.” The authors

A recent Brazilian study, “Increased Sympathetic and Hemodynamic Responses to Exercise and Muscle Metaboreflex Activation in Post-menopausal Women with Rheumatoid Arthritis“, that got notice in the New York Times (“Why Exercise Can Be So Draining in Rheumatoid Arthritis“) uncovered some interesting parallels and differences between RA and ME/CFS.

A hyperactive sympathetic nervous system (SNS) that can impact everything from sleep to pain to exercise intolerance is found in both. Besides the high rates of SNS activity at rest, studies indicate that people with RA have trouble turning their SNS off, leaving their heart rates and blood pressures elevated after exercise. One metareview simply states that RA is a disease characterized by “parasympathetic autonomic dysfunction which is related to inflammation”. The autonomic problems found in RA are believed to be at least partly responsible for the increased risk of cardiovascular diseases found in RA.

This study took 43 older women (33 with, and 10 without RA), drew their blood, gave them questionnaires, and tested their blood pressure. They also embedded small sensors in their muscles that assessed the metabolites produced by the muscles, before, during, and after exercise. The exercise, itself, was considered “light”, and consisted of a series of isometric leg extensions for 3 minutes at 30% of their maximal capacity.

As expected, the RA patients’ sympathetic nervous systems were activated and their baroreflex response – which controls heart rate and blood pressure – was blunted during rest. The light exercise sent their already hyperactive sympathetic nervous system into overdrive – sending their blood pressure soaring – perhaps in an effort to drive more blood to the muscles. Those blood pressure spikes, the authors believe, may underlie some of the cardiovascular problems found in RA.

One of the study’s novel findings was the possibly central role the immune system may be playing. It appeared that pro and anti-inflammatory factors (IFN-y, IL-8, MCP-1 and TNFα, IL-1ra, and IL-10) produced by the muscles during the exercise session may be triggering the SNS hyperactivity.

The metaboreflex may be activated in different ways in RA and ME/CFS.

Signs of an active metaboreflex were also found. The “muscle metaboreflex” occurs when metabolic receptors in the muscles (acid-sensing ion channels (ASIC), purinergic receptors (P2X), transient receptor potential cation channels of the vanilloid type 1 (TRPV1)) pick up indications that the aerobic capacity of the muscle has been overwhelmed.

These receptors sent signals to increase blood flows to the muscle – thus possibly triggering the sympathetic nervous system activation and increased blood pressure found.

The Gist

  • People with rheumatoid arthritis (RA) often feel drained and fatigued after exercise, but no one knows why.
  • Drugs that improve RA do little to affect the fatigue or exercise problems in it. Some sort of systemic problem that hasn’t been addressed seems to be in play.
  • Exercise triggers increased levels of sympathetic nervous system activity and causes blood pressure spikes that remain for unusually long periods.
  • This study had RA patients engage in quite mild exercises (leg raises) while monitoring their cardiovascular responses. It also embedded tiny sensors in their muscles, which identified the metabolites the muscles were producing.
  • Immune factors produced by the muscles during exercise were associated with the increased sympathetic nervous system (SNS) activity and blood pressure spikes.
  • The “metaboreflex”, which occurs when muscles become overwhelmed by exercise, also was present. The metaboreflex sends signals to provide more blood flows to the muscle. It may also be triggering the SNS activity.
  • The same metabolic receptors that Alan Light and company found were greatly upregulated in ME/CFS patients during exercise appeared to be upregulated in the RA patients as well.
  • Thus far, it appears that different processes are tweaking those receptors, though. In ME/CFS, it appears that a breakdown in cellular energy production is, while in RA, it appears that inflammatory cytokines are.
  • RA and ME/CFS, then, share similar biological processes (metaboreflex, high SNS activity) which trigger exercise intolerance. At their core, though, they may be quite different. Exercise intolerance is triggered in ME/CFS by problems with energy production, while it is triggered in RA by inflammation.
  • The authors reported that they’d also found problems with exercise intolerance in long COVID and expect to be reporting on that soon.

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Indeed, statistical analysis showed that the cytokine upregulation was “moderately associated” with the autonomic nervous system dysfunction (SNS activation) found. The sympathetic nervous system activation was, in turn, associated with increased pain.

The metaboreflex in RA, then, is being tricked by the immune system to portray a problem that’s not there. That “trick”, though, could have real consequences, as the authors believe it may be contributing to the cardiovascular problems found in RA.

ME/CFS and Rheumatoid Arthritis

Both conditions are associated with a hyperactive sympathetic nervous system, which in turn, is associated with increased levels of pain, fatigue, and blood circulation issues.

Wirth and Scheibenbogen, for instance, place heightened sympathetic nervous system activity at the core of ME/CFS. Increased sympathetic overdrive was also linked to an inability to complete an exercise program in ME/CFS. Likewise, sympathetic nervous system dominance has been documented in overtraining syndrome. High levels of systemic inflammation aren’t found in either of these conditions.

They are in RA. In the Brazilian study, the most impaired RA patients exhibited both increased sympathetic overdrive and depleted parasympathetic functioning – and the highest levels of inflammation.

Note that Alan Light’s MECFS gene expression and exercise study found the same metaboreflex receptor upregulation. Light proposed that high levels of muscle metabolites might be tweaking these receptors. Since then, numerous studies suggest that problems with energy production may exist.

The situation, at least at this point, appears to be markedly different in RA. Citing a 17-year-old study that did not find high levels of lactate in RA, the authors of the RA paper refused to go down the energy production rabbit hole. Instead, they proposed that inflammation was probably sensitizing the muscle metabolite receptors in RA. (This despite the fact that drugs that reduce inflammation in RA do little to improve RA patients’ fatigue.)

Thus, while the muscle metaboreflex appears to be turned on in both disorders – it appears that it’s turned on in different ways.

The result, while different in degree, is nevertheless similar – exercise activates the metaboreflex, which in turn, activates the SNS, producing pain and fatigue. Perhaps greater exercise intolerance in ME/CFS derives from the fact that it’s being produced both by energy production problems and sympathetic nervous system overdrive. In RA it’s produced mainly by sympathetic nervous system problems.

The Brazilian group has also found odd responses to exercise in people with long COVID.

There are probably only so many ways to produce exercise intolerance. Interestingly, RA and ME/CFS share some ways and not others. It’ll be fascinating to see the different permutations that crop up over time in different conditions.

The Brazilian authors managed to do something that I don’t believe has been done in ME/CFS: they embedded tiny sensors into the muscles and then tracked the changes that occurred in the muscles as the RA patients exercised.

While we don’t know what that would show in MECFS, we may soon get the next best thing. Dr. Roschel, the senior author of the study, stated that their exercise studies in long-COVID patients have found that “they also present abnormal cardiorespiratory responses to exercise“. Expect studies on that juicy topic to be published soon.

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